Beruflich Dokumente
Kultur Dokumente
Nutritional Epidemiology
Abstract
Background: Hepatic lipase (HL) plays a pivotal role in the metabolism of HDL and LDL. Recent genome-wide association
studies have identified common variants in the HL gene (LIPC) associated with HDL cholesterol.
Objective: We tested the effect of a common variant in LIPC on changes in blood lipids in response to weight-loss diets in
the Preventing Overweight Using Novel Dietary Strategies Trial.
Methods: We genotyped LIPC rs2070895 in 743 overweight or obese adults aged 30–70 y (61% women) who were
assigned to high-fat (40% energy) or low-fat (20% energy) diets for 2 y. We measured serum concentrations of total
cholesterol (TC), triglycerides, LDL cholesterol, and HDL cholesterol at baseline and 2 y of intervention.
Results: At 2 y of intervention, dietary fat modified effects of the variant on changes in serum TC, LDL cholesterol, and
HDL cholesterol (P-interaction: 0.0008, 0.004, and 0.03, respectively). In the low-fat group, as compared to the G allele, the
A allele tended to be related to the decrease in TC and LDL cholesterol concentrations [TC (b 6 SE): 25.5 6 3.0, P = 0.07;
LDL cholesterol: 24.8 6 2.5, P = 0.06] and a lower increase in HDL cholesterol concentrations (b 6 SE: 21.37 6 0.69, P =
0.048), whereas an opposite effect in the high-fat diet group was evident [TC (b 6 SE): 7.3 6 2.7, P = 0.008; LDL
cholesterol: 4.1 6 2.3, P = 0.07], and there was no genetic effect on changes in HDL cholesterol concentrations (P = 0.54).
Conclusion: Dietary fat intake modifies the effect of a common variant in LIPC on changes in serum lipids during a
long-term weight-loss intervention in overweight or obese adults. This trial was registered at clinicaltrials.gov as
NCT00072995. J Nutr 2015;145:1289–94.
Keywords: hepatic lipase, LIPC, high-fat diet, gene-diet interaction, weight-loss intervention
Introduction
cardiovascular risk. Hepatic lipase (HL)11, which is expressed in
Dyslipidemia, such as low HDL cholesterol, and high LDL the liver, plays a pivotal role in the metabolism of lipoproteins as
cholesterol and TGs, has been well associated with increased a lipolytic enzyme that hydrolyzes TGs and phospholipids in
chylomicron remnants, intermediate-density lipoprotein, and
1
Supported by grants from the National Heart, Lung, and Blood Institute
HDL. HL has a multifunctional effect on the development of
(HL071981), the National Institute of Diabetes and Digestive and Kidney Diseases atherosclerosis. Previous studies support proatherogenic and
(DK091718), the General Clinical Research Center (RR-02635), the Boston Obesity antiatherogenic functions for HL (1).Candidate gene studies
Nutrition Research Center (DK46200), the United States–Israel Binational Science have reported that variation in the HL gene (LIPC) affected the
Foundation (2011036), the National Natural Science Foundation of China (81270877
effectiveness of the therapy in reducing the risk of cardiovascular
and 81471062), and the Shanghai Pujiang Project (14PJD024). L Qi was a recipient
of the AHA Scientist Development Award (0730094N). disease (2, 3). Recent genome-wide association studies have
2
Author disclosures: M Xu, SS Ng, GA Bray, DH Ryan, FM Sacks, G Ning, and identified and confirmed a common variant rs2070895 in LIPC
L Qi, no conflicts of interest.
3
Supplemental Tables 1 and 2 are available from the ‘‘Online Supporting
Material’’ link in the online posting of the article and from the same link in the
online table of contents at http://jn.nutrition.org. 11
Abbreviations used: HL, hepatic lipase; LIPC, hepatic lipase gene; POUNDS
* To whom correspondence should be addressed. E-mail: nhlqi@channing. LOST, Preventing Overweight Using Novel Dietary Strategies; SNP, single
harvard.edu (L Qi), della.xumin@163.com (M Xu). nucleotide polymorphism; TC, total cholesterol.
and biomarkers of adherence to the assigned diet at 2 y across genetic variation and lipids. We did not find a significant
the LIPC rs2070895 genotype in low- and high-fat diet groups. difference in changes of TC after further adjustment for changes
The weight losses (means 6 SDs) in the high- and low-fat in LDL cholesterol at 2 y in the low-fat or high-fat groups. We
diet groups were 4.0 6 7.3 kg and 4.2 6 7.6 kg at 2 y, found opposite genetic effects on changes in HDL cholesterol
respectively. The corresponding weight losses among the 3 concentrations. The A allele was significantly associated with
genotypes of LIPC rs2070895 variant were 2.9 6 4.9 kg in the less increase of HDL cholesterol concentrations in the low-fat
AA, 3.8 6 7.6 kg in the GA, and 4.4 6 7.6 kg in the GG group (b 6 SE: 21.37 6 0.69, P = 0.048), whereas no
genotype at 2 y, respectively. No main genetic effect or gene- association was observed in the high-fat group (b 6 SE: 0.44 6
diet interaction was found on weight loss during 2 y of 0.71, P = 0.54). We did not detect any interactions between the
intervention. Genotype did not affect the changes in serum TC, genetic variation and dietary fat intake on changes in serum TG
LDL cholesterol, or HDL cholesterol concentrations during 2 y at 2 y of intervention (P-interaction: 0.62). Similar interactions
of intervention (all P $ 0.35). were observed when the analysis was restricted to the white
We then examined the interaction of dietary fat intake and participants (Supplemental Table 2).
the genetic variation on changes in serum lipids. At 2 y of We then examined the trajectory changes in lipids accord-
intervention, we observed that dietary fat significantly modified ing to the LIPC rs2070895 genotypes by dietary fat intake
the genetic effects of rs2070895 on changes in serum TC, LDL over the 2-y intervention period. We observed significant
cholesterol, and HDL cholesterol (P-interaction: 0.0008, 0.004, genotype-time interactions on changes in TC, LDL cholesterol,
and 0.03, respectively), with adjustment for age, sex, ethnicity, and HDL cholesterol in the low-fat diet group (P-interactions:
baseline BMI, weight loss, and baseline measurements for the 0.01, 0.01, and 0.005, respectively). The LIPC genetic effects
respective outcomes (Figure 1, Table 2). In the low-fat diet on TC and LDL cholesterol displayed a cumulative pattern
group, the A allele was associated with a decrease of TC and throughout the intervention and reached the maximum values
LDL cholesterol concentrations [TC (b 6 SE): 25.5 6 3.0, P = at 2 y (all P-trend values were #0.002 for AA and AG
0.07; LDL cholesterol: 24.8 6 2.5, P = 0.06], whereas an genotype, but there were no significant trends for GG
opposite genetic effect was found in the high-fat diet group [TC genotype), whereas continued cumulative increasing trends
(b 6 SE): 7.3 6 2.7, P = 0.008; LDL cholesterol: 4.1 6 2.3, P = were found in HDL cholesterol concentrations (both P-trend
0.07]. Then we tested the independent associations between the values were #0.0001 for GG and AG genotype, but there were
Diet modifies LIPC gene effect on serum lipids 1291
FIGURE 1 Trajectory analysis on 2-y
changes in serum total cholesterol (A, D),
LDL cholesterol (B, E), and HDL cholesterol
(C, F) by LIPC rs2070895 genotype of
participants that consumed the low-fat (up-
per panels) or high-fat (lower panels) diets.
The number of participants in the low-fat diet
group (A–C), for AA: n = 30 at baseline, n =
22 at 6 mo, and n = 20 at 2 y; AG: n = 138 at
baseline, n = 118 at 6 mo, and n = 101 at 2 y;
and GG: n = 204 at baseline, n = 182 at 6
mo, and n = 155 at 2 y. The corresponding
numbers in the high-fat diet group (D–F), AA:
n = 32, 24, and 20, at baseline, 6 mo, and
2 y, respectively; AG: n = 130, 110, and 98,
at baseline, 6 mo, and 2 y, respectively; and
GG: n = 209,180, and 149, at baseline, 6 mo,
no significant trends for GG genotype) (Figure 1A–C). In the allele. In the current study, the minor allele A was associated
high-fat diet group, we observed a significant genotype-time with less of an increase in HDL cholesterol in response to a low-
interaction on changes in TC (P-interaction: 0.03), a marginal fat diet. Our data suggest that LIPC may partly account for the
interaction on changes in LDL cholesterol (P-interaction: 0.06), interindividual heterogeneity in HDL cholesterol changes in-
and no significant interaction on changes in HDL cholesterol (P- duced by different dietary fat intake, although the underlying
interaction: 0.68) (Figure 1D–F). mechanisms remain to be determined.
In addition to HDL cholesterol, we also found that dietary fat
intake significantly modified the genetic effect of LIPC on
Discussion changes in TC and LDL cholesterol concentrations during the
In this 2-y randomized weight-loss intervention trial, we weight-loss trial. Our results were consistent with previous
observed a significant interaction between the LIPC SNP investigation (19). Lindi et al. (19) reported that individuals with
rs2070895 and dietary fat intake on changes in serum TC, the AA genotype were responsive to the multiunsaturated FA–
LDL cholesterol, and HDL cholesterol concentrations. The A enriched diet, and their serum LDL cholesterol concentrations
allele was related to a decrease in TC and LDL cholesterol and a decreased more than in subjects with other genotypes. Interest-
small increase in HDL cholesterol in response to the low-fat diet, ingly, we found that the genetic effect on changes in TC and LDL
whereas an opposite genetic effect was observed when partic- cholesterol in response to a low-fat diet showed a cumulative
ipants were assigned a high-fat diet. The genetic effect on pattern throughout the intervention and reached the maximum
changes of blood cholesterol concentrations showed a long-
term, cumulative pattern throughout the intervention. TABLE 2 Dietary fat intakes modulated the genotype effect of
Our findings are in line with several previous studies. These the LIPC rs2070895 variant on the changes in lipids in response to
studies have reported that the effects of 2514C/T (rs1800588) the dietary fat intervention at 2 y1
of LIPC, which is in high linkage disequilibrium with rs2070895
Low-fat diet High-fat diet P-interaction
(r2 = 0.97), on HDL cholesterol concentrations were modified by
dietary fat intake (7, 10, 11). Like rs2070895, rs1800588 is DTotal cholesterol, mg/dL
2
located in the promoter region and associated with decreased AA 20 (224.7 6 8.2) 20 (7.4 6 9.5)
plasma HL activity and increased HDL cholesterol concentra- AG 101 (215.0 6 5.2) 98 (1.3 6 7.8)
tions (3, 16, 17). In the Framingham Study, the T allele (in GG 155 (211.2 6 5.2) 149 (26.3 6 7.6)
linkage disequilibrium with allele A in rs2070895) was associ- P-trend3 0.07 0.008 0.0008
ated with significantly higher HDL cholesterol concentrations DLDL cholesterol,2 mg/dL
and large particle size only in subjects consuming 30% of energy AA 20 (221.8 6 6.8) 20 (10.7 6 8.1)
from fat (10). The study indicated an intraindividual difference AG 101 (211.2 6 4.3) 98 (6.3 6 6.7)
in the plasma lipid response to the dietary fat. Similar results GG 155 (28.7 6 4.3) 149 (2.1 6 6.5)
were found in African Americans (16) and subjects of Indian P-trend3 0.06 0.07 0.004
origin living in Singapore (11). DHDL cholesterol,2 mg/dL
However, few studies have assessed interactions between AA 20 (2.73 6 1.85) 20 (5.67 6 2.42)
LIPC genotype and dietary factors in intervention trials (18). In AG 101 (3.32 6 1.16) 98 (9.02 6 1.99)
the Finnish Diabetes Prevention Study (18), the A allele was GG 155 (4.81 6 1.16) 149 (7.09 6 1.95)
associated with a low conversion rate to type 2 diabetes in the P-trend3 0.048 0.54 0.03
lifestyle intervention group, which was assigned to a reduced fat
intake of <30% of energy consumed and reduced intake of
1
Values are n (means 6 SEs). LIPC, hepatic lipase gene.
2
The D variables indicate the change of respective outcomes.
saturated fat to <10% of energy consumed. In addition, a greater 3
P-trend was for general linear regression in which an additive genetic model was
increase in HDL cholesterol concentration from baseline to 3 y analyzed for the rs2070895 variant. The adjustment was including age, sex, ethnicity,
was found in subjects carrying the A allele than those with the G baseline BMI, weight loss, and baseline values for respective outcomes.
1292 Xu et al.
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